PAPP-A as a marker of increased long-term risk in patients with chest pain

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Abstract

Objectives

Long-term risk stratification in patients presenting with acute coronary syndromes (ACS) is possible by measuring cardiac troponin (cTn). The present study examined whether PAPP-A measured in an emergency department (ED) chest pain population in association with conventional and novel high sensitivity cTn (hs-cTnI) assays can predict long-term mortality.

Methods

In 320 patients with cTn measurements the earliest heparinized plasma PAPP-A concentration after presentation was used for risk stratification for death by Kaplan–Meier and Cox analyses. Subgroup analyses using the earliest PAPP-A concentrations were also performed in a cohort of subjects with presentation cTnI ≤ 99th percentile but with significantly changing cardiac troponin concentrations as measured by the AccuTnI assay and the hs-cTnI assay (n = 45 and 120 subjects, respectively).

Results

Subjects with PAPP-A concentrations in the highest tertile were at higher risk for death (HR > 2.00; p  0.05 at 2 years) even after adjusting for cTnI at presentation. In the cohort with cTnI  99th percentile but with changing hs-cTnI concentrations, subjects in the top PAPP-A tertile had a higher probability for death (p = 0.02).

Conclusion

Early measurement of PAPP-A may identify chest pain patients at higher risk for long-term death. Additional prospective ACS studies are required to fully elucidate PAPP-A's role.

Introduction

Acute coronary syndromes (ACS) including unstable angina, non-ST and ST-elevation myocardial infarction are the leading causes of mortality and morbidity worldwide [1], [2]. Despite sophisticated imaging technology and biochemical markers to assist in the diagnosis and monitoring of ACS patients, there still are patients who are inaccurately diagnosed in the emergency department (ED) and others whose risk of adverse events following presentation is underestimated [3], [4], [5], [6], [7]. The use of sensitive troponin assays has helped with better diagnosis [8], but additional biomarkers would be especially useful to identify patients at long-term risk after presentation. A few acute-care markers such as cardiac troponin (cTn), natriuretic peptides and C-reactive protein (CRP), have been shown to have longer-term predictive value in patients with ACS [7], [9], [10], [11], [12], [13], [14], [15], [16] but there are additional patients at risk who are not identified, perhaps in part because none of these biomarkers provides information about atherosclerotic plaque instability. A sensitive and specific early biomarker of atherosclerotic plaque instability would assist in risk stratification. Vulnerable coronary atherosclerotic plaques have been reported to contain pregnancy associated plasma protein-A (PAPP-A) [17], [18]. Since these lesions appear to precede the development of myocardial ischemia and necrosis, PAPP-A could serve as a useful marker both for early diagnosis of ACS and to define those without acute events who are at subsequent risk for events [18], [19]. In the present study, we used a new high-sensitivity PAPP-A (hsPAPP-A) assay to assess both the analytical and clinical utility of PAPP-A in an emergency department chest pain population characterized with a conventional sensitive cTnI assay and new research high-sensitivity cTnI (hs-cTnI) assay.

Section snippets

Study population and laboratory analyses

The study population has been previously described [14], [15], [20], [21], [22]. Briefly, in 1996 after research ethics approval, 458 patients representing 500 separate patient presentations to the ED were enrolled in a Cardiac Markers study. The only inclusion criterion was the assessment by the triage staff that the patient had symptoms suggestive of cardiac ischemia; there were no exclusion criteria. Heparin plasma samples were collected at presentation and at scheduled intervals measured

Results

The median age was 64 years for the study population (n = 320 with 60% men; see Table 1). The values for PAPP-A appear to manifest a rise during the first 9 h after pain onset but there is a considerable overlap in PAPP-A ranges between the different time points (Fig. 2A). There was no difference in the initial PAPP-A concentrations in those who received (n = 70) and did not receive heparin (n = 250) during their hospital stay (median (IQR) PAPP-A = 1.22 (0.80–1.99) vs. 1.20 (0.79–1.97) mIU/L; p = 0.68),

Discussion

PAPP-A is a 200 kDa metalloproteinase that circulates in distinct forms during pregnancy and ACS [25]. During pregnancy, PAPP-A circulates as a heterodimer with the pro-form of eosinophil major basic protein (proMBP). Bound proMBP acts as a protease inhibitor [19], [26]. PAPP-A is found in unstable plaques, however the physiological role of PAPP-A in the atherosclerotic plaque is not clear. One hypothesis is that PAPP-A secretion is a repair mechanism involved in plaque stabilization. PAPP-A is

Acknowledgments

This study was funded by CIHR. Reagents were provided as an unrestricted grant by Beckman Coulter. Special thanks to Dr. Ed Young for input on heparin therapy and the Clinical Research and Clinical Trials Laboratory, Hamilton for performing the biomarker measurements.

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